in developing methods for the stereoselective synthesis of
3,3-disubstituted 2-azanorbornyl derivatives 2 (Figure 1).
Recently, much interest has been directed toward the
stereoselective alkylation of both endo- and exo-heterocyclic
enolates8 and in the origin of the high degrees of π-facial
selectivity (>95%) usually observed in these reactions.9 As
a consequence, this research has found several applications
in the synthesis of enantiomerically pure alkylated amino
acid analogues8 as well as in the preparation of naturally
ocurring compounds.10
Scheme 2. Reaction of Enolate 5 with Electrophiles
Here we report on the diastereoselective reaction of
exocyclic enolate 5 with different electrophiles at low
temperature which allows the synthesis of new 3,3-disub-
stituted bicyclic derivatives 6 which should be potential chiral
ligands for a wide number of catalytic asymmetric reactions.
The starting bicyclic amino ester 4 was easily prepared in
high yield as outlined in Scheme 1. Hydrogenation/hydro-
for 1 h.13 The intermediate enolate 5 (Scheme 2) was then
reacted with a number of different electrophiles. The results
are summarized in Table 1.
Treatment of 5 with water afforded a 70/30 mixture of
endo/exo diastereoisomers due to the protonation from the
less hindered exo face of the enolate14 (Table 1, entry 1).
The absolute configuration of the major isomer endo-4 was
confirmed by NOE experiments which clearly showed the
new endo arrangement for the methyl ester substituent
(Figure 2).
Scheme 1. Synthesis of Amino Ester 4
genolysis of compound 311 followed by alkylation with
benzyl bromide in acetonitrile afforded 4 in a 80% overall
yield from 3.
Figure 2. Selected NOE (%) observed for endo-4 and 6a.
At first, we attempted to alkylate 312 using LDA as base
and benzyl bromide as electrophile. However, this only led
to very low conversions even when high reaction tempera-
tures or large excess of base and/or electrophile were used.
This is probably due to a very slow deprotonation of the
sterically encumbered ester.
On the other hand, enolate 5 reacted with very high levels
of diastereoselectivity at the less hindered exo face,15 with a
wide range of different electrophiles (alkyl halides, alde-
hydes, acid derivatives, and Michael aceptors) to afford the
bicyclic exo-addition products 6 with good yields and >95%
d.e. in all cases (Table 1). Absolute configurations at C3 for
all new compounds 6a-j were confirmed by NOE experi-
On the other hand, compound 4 was readily deprotonated
when treated with freshly prepared LDA at -20 °C in THF
(5) (a) Nakano, H.; Kumagai, N.; Kabuto, Ch.; Matsuzaki, H.; Hongo,
H. Tetrahedron: Asymmetry 1997, 8, 1391. (b) So¨dergren, M. J.; Andersson,
P. G. Tetrahedron Lett. 1996, 37, 7577. (c) Pinho, P.; Guijarro, D.;
Andersson, P. G. Tetrahedron 1998, 54, 7897. (d) So¨dergren, M. J.;
Andersson, P. G. J. Am. Chem. Soc. 1998, 120, 10760.
(6) (a) Alonso, D. A.; Guijarro, D.; Pinho, P.; Temme, O.; Andersson,
P. G. J. Org. Chem. 1998, 63, 2749. (b) Alonso, D. A.; Brandt, P.; Nordin,
S. J. M.; Andersson, P. G. J. Am. Chem. Soc. 1999, in press.
(7) (a) Guijarro, D.; Pinho, P.; Andersson, P. G. J. Org. Chem. 1998,
63, 3, 2530. (b) Brandt, P.; Hedberg, C.; Lawonn, K.; Pinho, P.; Andersson,
P. G. Chem. Eur. J. 1999, 5, 1692.
(8) (a) Zhang, R.; Brownewell, F.; Madalengoitia, J. S. Tetrahedron Lett.
1999, 40, 2707. (b) Nagumo, Sh.; Mizukami, M.; Akutsu, N.; Nishida, A.;
Kawahara, N. Tetrahedron Lett. 1999, 40, 3209.
(9) (a) Meyers, A. I.; Seefeld, M. A.; Lefker, B. A.; Blake, J. F. J. Am.
Chem. Soc. 1997, 119, 4565. (b) Meyers, A. I.; Seefeld, M. A.; Lefker, B.
A.; Blake, J. F.; Williard, P. G. J. Am. Chem. Soc. 1998, 120, 7429. (c)
Ando, K.; Green, N. S.; Li, Y.; Houk, K. N. J. Am. Chem. Soc. 1999, 121,
5334 and references therein.
(13) Typical Experimental Procedure. A solution of compound 4 (100
mg, 0.41 mmol) in dry THF (1 mL) was slowly added to a solution of
freshly prepared LDA (0.45 mmol) in dry THF (5 mL) at -20 °C. After
40 min of stirring the corresponding electrophile was added (0.43 mmol)
at -5 °C, and the mixture was allowed to reach room-temperature overnight.
The reaction was quenched with a saturated aqueous solution of NaCl and
extracted with Et2O (3 × 20 mL). The combined organic extracts were
dried (MgSO4) and evaporated, and the residue was purified by flash
chromatography (silica gel, pentane/ether) to afford compounds 6. Yields
and physical data are included in Table 1. Spectral and analytical data for
compound 6j are as follows: [R]21D ) -4.5 (c ) 0.11, CH2Cl2); 1H NMR
(400 MHz/CDCl3) δ 1.27-1.40, 1.48-1.59, 1.90-1.98 (6H, 3m), 3.03 (1H,
br s), 3.09 (1H, s), 3.73 (3H, s), 3.76 (3H, s), 4.20 (2H, s), and 7.19-7.32
(5H, m); 13C NMR (100 MHz, CDCl3) δ 23.8, 25.1, 38.4, 45.8, 49.7, 51.9,
52.0, 57.7, 126.5, 127.9, 128.1, 141.6, 170.2, and 171.7; IR (neat, cm-1
)
2949, 1738, 1264, 1213, 1161, and 1105; MS (EI) m/z (rel intensity) 304
(M+ + 1, <1%), 303 (M+, 2), 245 (20), 244 (100), 216 (65), 184 (11), and
91 (54). Anal. Calcd for C17H21NO4: C, 67.31; H, 6.98; N, 4.62. Found:
C, 67.25; H, 7.04; N, 4.71.
(14) Attempts to increase this selectivity by the use of lower temperatures,
different bulkier proton sources such as i-PrOH, t-BuOH, PhOH, or via
acidic workup with 1 M HCl only led to lower or similar levels of
diastereoselection.
(10) Arrington, M. P.; Meyers, A. I. Chem. Commun. 1999, 1371.
(11) Compound 3 is obtained in high yield via a highly exo-selective
and diastereoselective aza-Diels-Alder reaction between cyclopentadiene
and the iminium ion derived from ethyl glyoxylate and (S)-1-phenylethy-
lamine. See ref 2a.
(12) For methylation of the racemic N-benzyl derivative of 3 and its use
in the synthesis of cyclopentyl glycine derivatives, see: Bourgeois-Cury,
A.; Doan, D.; Gore, J. Tetrahedron Lett. 1992, 33, 1277.
(15) Meyers and Houk have explain the observed π-facial stereoselec-
tivity in the alkylations of some particular heterocyclic enolates based on
electronic and steric effects or torsional strain and steric effects. See ref 9.
1596
Org. Lett., Vol. 1, No. 10, 1999